The overall goal of this Program Project is to elucidate the role of a novel family of genes that we recently discovered called Tims, in the pathogenesis of asthma. The Tim genes appear to play a critical role in regulating CD4 T cell differentiation and the development of allergen-induced airway hyperreactivity. In addition, we hypothesize that the human homologues of the Tim genes are asthma susceptibility genes, since they lie on chromosome 5q33.2, a region repeatedly linked to asthma, and display significant sequence polymorphisms. Moreover, the human Tim1 encodes the receptor for the hepatitis A virus (HAV), suggesting that CD4 T cells and TIM-1 mediate the known protective effect of prior infection with HAV on the development of atopy. Since the prevalence of HAV infection is greatly reduced in industrialized countries, our findings may explain the increase in asthma prevalence occurring over the past decades, and strongly suggest that Tim1 plays a major role in directly regulating the development of human asthma and allergy. The proposed studies will examine several members of the Tim gene family in both human and murine systems. In Project 1, headed by Dale T. Umetsu, we will perform association analysis to determine if Tim1 and Tim3 gene polymorphisms are associated with asthma, allergy, specific IgE, or elevated total IgE. We will also analyze the cellular and molecular processes that occur when HAV binds to TIM-1 on T lymphocytes, and determine how HAV infection alters CD4 T cell differentiation and prevents the development of asthma. In Project 2, headed by Gordon J. Freeman, we will examine the expression pattern of human TIM-1 and TIM-3, and examine the function of human TIM-1 and TIM-3 using TIM-1 and TIM-3 fusion proteins, as well as antibody directed against these proteins. In addition, we will characterize the ligand for TIM-3 and TIM-1. In Project 3, headed by Rosemarie H. DeKruyff, we will utilize a murine system with Tim1 knockout mice and TIM blocking reagents to directly study the precise role of TIM-1 in the development of Th2 responses and allergen-induced airway hyperreactivity. This Program Project brings together a group of very strong immunologists, who have worked closely together for many years, along with an outstanding geneticist and virologist. Together, these investigators have a very strong record of accomplishment in asthma and allergy, cloning genes and their ligands, and in investigating the genetics of complex disease. These studies of Tim genes will characterize a very important human asthma susceptibility gene, and provide extraordinary insight into genetic, immunologic and environmental pathways involved in asthma pathogenesis.